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Losartan Potassium and Hydrochlorothiazide Tablets

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 


USE IN PREGNANCY

When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, losartan/hydrochlorothiazide should be discontinued as soon as possible.



1. DESCRIPTION

Losartan and hydrochlorothiazide tablet combines an angiotensin II receptor (type AT1) antagonist, losartan potassium, and a diuretic, hydrochlorothiazide.

Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt. Its empirical formula is C22H22ClKN6O, and its structural formula is:

Losartan potassium is a white to off-white free-flowing crystalline powder with a molecular weight of 461.01. It is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as acetonitrile and methyl ethyl ketone.

Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan.

Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8ClN3O4S2 and its structural formula is:

Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.74, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.

Losartan/hydrochlorothiazide is available for oral administration in three tablet combinations of losartan and hydrochlorothiazide. Losartan/hydrochlorothiazide 50-12.5 contains 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide. Losartan/hydrochlorothiazide 100-12.5 contains 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide. Losartan/hydrochlorothiazide 100-25 contains 100 mg of losartan potassium and 25 mg of hydrochlorothiazide. Inactive ingredients are microcrystalline cellulose, lactose hydrous, pregelatinized starch, magnesium stearate, hydroxypropyl cellulose, hypromellose, and titanium dioxide.

Losartan/hydrochlorothiazide 50-12.5 and losartan/hydrochlorothiazide 100-25 also contain D&C yellow No. 10 aluminum lake. Losartan/hydrochlorothiazide 50-12.5, losartan/hydrochlorothiazide 100-12.5, and losartan/hydrochlorothiazide 100-25 may also contain carnauba wax.

Losartan/hydrochlorothiazide 50-12.5 contains 4.24 mg (0.108 mEq) of potassium, losartan/hydrochlorothiazide 100-12.5 contains 8.48 mg (0.216 mEq) of potassium, and losartan/hydrochlorothiazide 100-25 contains 8.48 mg (0.216 mEq) of potassium.

2. INDICATIONS AND USAGE

2.1 Hypertension

Losartan/hydrochlorothiazide is indicated for the treatment of hypertension. This fixed dose combination is not indicated for initial therapy of hypertension, except when the hypertension is severe enough that the value of achieving prompt blood pressure control exceeds the risk of initiating combination therapy in these patients (see DOSAGE AND ADMINISTRATION).

2.2 Hypertensive Patients with Left Ventricular Hypertrophy

Losartan/hydrochlorothiazide is indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to Black patients. (See PRECAUTIONS, Race, and DOSAGE AND ADMINISTRATION.)

3. DOSAGE AND ADMINISTRATION

3.1 Hypertension

Dosing must be individualized. The usual starting dose of losartan is 50 mg once daily, with 25 mg recommended for patients with intravascular volume depletion (e.g., patients treated with diuretics) and patients with a history of hepatic impairment. Losartan can be administered once or twice daily at total daily doses of 25 to 100 mg. If the antihypertensive effect measured at trough using once-aday dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response.

Hydrochlorothiazide is effective in doses of 12.5 to 50 mg once daily and can be given at doses of 12.5 to 25 mg as losartan/hydrochlorothiazide.

To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.

The side effects (see WARNINGS) of losartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of losartan and hydrochlorothiazide will be associated with both sets of dose-independent side effects.

Replacement Therapy: The combination may be substituted for the titrated components.

Dose Titration by Clinical Effect: A patient whose blood pressure is not adequately controlled with losartan monotherapy or hydrochlorothiazide alone, may be switched to losartan/hydrochlorothiazide 50-12.5 (losartan 50 mg/hydrochlorothiazide 12.5 mg) once daily. If blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to two tablets of losartan/hydrochlorothiazide 50-12.5 once daily or one tablet of losartan/hydrochlorothiazide 100-25 (losartan 100 mg/hydrochlorothiazide 25 mg) once daily. A patient whose blood pressure is not adequately controlled with losartan 100 mg monotherapy may be switched to losartan/hydrochlorothiazide 100-12.5 once daily. If blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to two tablets of losartan/hydrochlorothiazide 50-12.5 once daily or one tablet of losartan/hydrochlorothiazide 100-25 (losartan 100 mg/hydrochlorothiazide 25 mg) once daily.

A patient whose blood pressure is inadequately controlled by 25 mg once daily of hydrochlorothiazide, or is controlled but who experiences hypokalemia with this regimen, may be switched to losartan/hydrochlorothiazide 50-12.5 (losartan 50 mg/hydrochlorothiazide 12.5 mg) once daily, reducing the dose of hydrochlorothiazide without reducing the overall expected antihypertensive response. The clinical response to losartan/hydrochlorothiazide 50-12.5 should be subsequently evaluated, and if blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to two tablets of losartan/hydrochlorothiazide 50-12.5 once daily or one tablet of losartan/hydrochlorothiazide 100-25 (losartan 100 mg/hydrochlorothiazide 25 mg) once daily.

The usual dose of losartan/hydrochlorothiazide is one tablet of losartan/hydrochlorothiazide 50-12.5 once daily. More than two tablets of losartan/hydrochlorothiazide 50-12.5 once daily or more than one tablet of losartan/hydrochlorothiazide 100-25 once daily is not recommended. The maximal antihypertensive effect is attained about 3 weeks after initiation of therapy.

Use in Patients with Renal Impairment: The usual regimens of therapy with losartan/hydrochlorothiazide may be followed as long as the patient's creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so losartan/hydrochlorothiazide is not recommended.

Patients with Hepatic Impairment: Losartan/hydrochlorothiazide is not recommended for titration in patients with hepatic impairment because the appropriate 25 mg starting dose of losartan cannot be given.

3.2 Severe Hypertension

The starting dose of losartan/hydrochlorothiazide for initial treatment of severe hypertension is one tablet of losartan/hydrochlorothiazide 50-12.5 once daily. For patients who do not respond adequately to losartan/hydrochlorothiazide 50-12.5 after 2 to 4 weeks of therapy, the dosage may be increased to one tablet of losartan/hydrochlorothiazide 100-25 once daily. The maximum dose is one tablet of losartan/hydrochlorothiazide 100-25 once daily.

Losartan/hydrochlorothiazide is not recommended as initial therapy in patients with hepatic impairment because the appropriate 25 mg starting dose of losartan cannot be given. It is also not recommended for use as initial therapy in patients with intravascular volume depletion (e.g., patients treated with diuretics).

3.3 Hypertensive Patients with Left Ventricular Hypertrophy

Treatment should be initiated with losartan 50 mg once daily. Hydrochlorothiazide 12.5 mg should be added or losartan/hydrochlorothiazide 50-12.5 substituted if the blood pressure reduction is inadequate. If additional blood pressure reduction is needed, losartan 100 mg and hydrochlorothiazide 12.5 mg or losartan/hydrochlorothiazide 100-12.5 may be substituted, followed by losartan 100 mg and hydrochlorothiazide 25 mg or losartan/hydrochlorothiazide 100-25. For further blood pressure reduction other antihypertensives should be added.

Losartan/hydrochlorothiazide may be administered with other antihypertensive agents.

Losartan/hydrochlorothiazide may be administered with or without food.

4. CONTRAINDICATIONS

Losartan/hydrochlorothiazide is contraindicated in patients who are hypersensitive to any component of this product.

Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Do not co-administer aliskiren with losartan/hydrochlorothiazide in patients with diabetes.

5. MECHANISM OF ACTION

Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)], is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues (e.g., vascular smooth muscle, adrenal gland). There is also an AT2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT1 receptor and have much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2 receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT1 receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor.

Neither losartan nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin); nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.

The mechanism of the antihypertensive effect of thiazides is unknown.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Categories C (first trimester) and D (second and third trimesters).

See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

6.2 Nursing Mothers

It is not known whether losartan is excreted in human milk, but significant levels of losartan and its active metabolite were shown to be present in rat milk. Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

6.3 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

6.4 Geriatric Use

In a controlled clinical study for the reduction in the combined risk of cardiovascular death, stroke and myocardial infarction in hypertensive patients with left ventricular hypertrophy, 2857 patients (62%) were 65 years and over, while 808 patients (18%) were 75 years and over. In an effort to control blood pressure in this study, patients were coadministered losartan and hydrochlorothiazide 74% of the total time they were on study drug. No overall differences in effectiveness were observed between these patients and younger patients. Adverse events were somewhat more frequent in the elderly compared to non-elderly patients for both the losartan and hydrochlorothiazide and the control groups.

6.5 Race

In the LIFE study, Black patients with hypertension and left ventricular hypertrophy had a lower risk of stroke on atenolol than on losartan (both cotreated with hydrochlorothiazide in the majority of patients). Given the difficulty in interpreting subset differences in large trials, it cannot be known whether the observed difference is the result of chance. However, the LIFE study does not provide evidence that the benefits of losartan on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to Black patients.

7. WARNINGS AND PRECAUTIONS

WARNINGS

Fetal/Neonatal Morbidity and Mortality

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, losartan/hydrochlorothiazide should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.

Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of losartan/hydrochlorothiazide as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, losartan/hydrochlorothiazide should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

There was no evidence of teratogenicity in rats or rabbits treated with a maximum losartan potassium dose of 10 mg/kg/day in combination with 2.5 mg/kg/day of hydrochlorothiazide. At these dosages, respective exposures (AUCs) of losartan, its active metabolite, and hydrochlorothiazide in rabbits were approximately 5, 1.5, and 1.0 times those achieved in humans with 100 mg losartan in combination with 25 mg hydrochlorothiazide. AUC values for losartan, its active metabolite and hydrochlorothiazide, extrapolated from data obtained with losartan administered to rats at a dose of 50 mg/kg/day in combination with 12.5 mg/kg/day of hydrochlorothiazide, were approximately 6, 2, and 2 times greater than those achieved in humans with 100 mg of losartan in combination with 25 mg of hydrochlorothiazide. Fetal toxicity in rats, as evidenced by a slight increase in supernumerary ribs, was observed when females were treated prior to and throughout gestation with 10 mg/kg/day losartan in combination with 2.5 mg/kg/day hydrochlorothiazide. As also observed in studies with losartan alone, adverse fetal and neonatal effects, including decreased body weight, renal toxicity, and mortality, occurred when pregnant rats were treated during late gestation and/or lactation with 50 mg/kg/day losartan in combination with 12.5 mg/kg/day hydrochlorothiazide. Respective AUCs for losartan, its active metabolite and hydrochlorothiazide at these dosages in rats were approximately 35, 10 and 10 times greater than those achieved in humans with the administration of 100 mg of losartan in combination with 25 mg hydrochlorothiazide. When hydrochlorothiazide was administered without losartan to pregnant mice and rats during their respective periods of major organogenesis, at doses up to 3000 and 1000 mg/kg/day, respectively, there was no evidence of harm to the fetus.

Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Hypotension — Volume-Depleted Patients

In patients who are intravascularly volume-depleted (e.g., those treated with diuretics), symptomatic hypotension may occur after initiation of therapy with losartan/hydrochlorothiazide. These conditions should be corrected prior to administration of losartan/hydrochlorothiazide, or a lower starting dose should be used (see DOSAGE AND ADMINISTRATION).

Impaired Hepatic Function

Losartan Potassium-Hydrochlorothiazide

Losartan/hydrochlorothiazide is not recommended for patients with hepatic impairment who require titration with losartan. The lower starting dose of losartan recommended for use in patients with hepatic impairment cannot be given using losartan/hydrochlorothiazide.

Hydrochlorothiazide

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Hypersensitivity Reaction

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

Systemic Lupus Erythematosus

Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

Lithium Interaction

Lithium generally should not be given with thiazides (see PRECAUTIONS, Drug Interactions, Hydrochlorothiazide, Lithium).

Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

PRECAUTIONS

General

Hypersensitivity: Angioedema. See ADVERSE REACTIONS, Post-Marketing Experience.

Losartan Potassium-Hydrochlorothiazide

In double-blind clinical trials of various doses of losartan potassium and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.5 mEq/L) was 6.7% versus 3.5% for placebo; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4%. No patient discontinued due to increases or decreases in serum potassium. The mean decrease in serum potassium in patients treated with various doses of losartan and hydrochlorothiazide was 0.123 mEq/L. In patients treated with various doses of losartan and hydrochlorothiazide, there was also a dose-related decrease in the hypokalemic response to hydrochlorothiazide as the dose of losartan was increased, as well as a dose-related decrease in serum uric acid with increasing doses of losartan.

Hydrochlorothiazide

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy.

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy. Because losartan decreases uric acid, losartan in combination with hydrochlorothiazide attenuates the diuretic-induced hyperuricemia.

In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.

The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient. If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy.

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been reported in susceptible individuals treated with losartan/hydrochlorothiazide; in some patients, these changes in renal function were reversible upon discontinuation of therapy.

In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with losartan/hydrochlorothiazide.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. Similar effects have been reported with losartan/hydrochlorothiazide; in some patients, these effects were reversible upon discontinuation of therapy.

Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

Information for Patients

Pregnancy: Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to drugs that act on the renin-angiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.

Symptomatic Hypotension: A patient receiving losartan/hydrochlorothiazide should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patients should be told that if syncope occurs, losartan/hydrochlorothiazide should be discontinued until the physician has been consulted.

All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.

Potassium Supplements: A patient receiving losartan/hydrochlorothiazide should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician (see PRECAUTIONS, Drug Interactions, Losartan Potassium).

8. ADVERSE REACTIONS

Losartan potassium and hydrochlorothiazide has been evaluated for safety in 858 patients treated for essential hypertension and 3889 patients treated for hypertension and left ventricular hypertrophy. In clinical trials with losartan potassium and hydrochlorothiazide, no adverse experiences peculiar to this combination have been observed. Adverse experiences have been limited to those that were reported previously with losartan potassium and/or hydrochlorothiazide. The overall incidence of adverse experiences reported with the combination was comparable to placebo.

In general, treatment with losartan potassium-hydrochlorothiazide was well tolerated. For the most part, adverse experiences have been mild and transient in nature and have not required discontinuation of therapy. In controlled clinical trials, discontinuation of therapy due to clinical adverse experiences was required in only 2.8% and 2.3% of patients treated with the combination and placebo, respectively.

In controlled clinical trials, the following adverse experiences reported with losartan-hydrochlorothiazide occurred in ≥1 percent of patients, and more often on drug than placebo, regardless of drug relationship:

Table 1. Adverse Events Occured in ≥ 1 % of Patients

The following adverse events were also reported at a rate of 1% or greater, but were as, or more, common in the placebo group in studies of essential hypertension: asthenia/fatigue, diarrhea, nausea, headache, bronchitis, pharyngitis.

Adverse events occurred at about the same rates in men and women. Adverse events were somewhat more frequent in the elderly compared to non-elderly patients and somewhat more frequent in Blacks compared to non-Blacks for both the losartan-hydrochlorothiazide and the control groups.

A patient with known hypersensitivity to aspirin and penicillin, when treated with losartan potassium, was withdrawn from study due to swelling of the lips and eyelids and facial rash, reported as angioedema, which returned to normal 5 days after therapy was discontinued.

Superficial peeling of palms and hemolysis were reported in one subject treated with losartan potassium.

Losartan Potassium

Other adverse experiences that have been reported with losartan, without regard to causality, are listed below:

Body as a Whole: chest pain, facial edema, fever, orthostatic effects, syncope;

Cardiovascular: angina pectoris, arrhythmias including atrial fibrillation, sinus bradycardia, tachycardia, ventricular tachycardia and ventricular fibrillation, CVA, hypotension, myocardial infarction, second degree AV block;

Digestive: anorexia, constipation, dental pain, dry mouth, dyspepsia, flatulence, gastritis, vomiting;

General disorders and administration site conditions: malaise;

Hematologic: anemia;

Metabolic: gout;

Musculoskeletal: arm pain, arthralgia, arthritis, fibromyalgia, hip pain, joint swelling, knee pain, leg pain, muscle cramps, muscle weakness, musculoskeletal pain, myalgia, shoulder pain, stiffness;

Nervous System/Psychiatric: anxiety, anxiety disorder, ataxia, confusion, depression, dream abnormality, hypesthesia, insomnia, libido decreased, memory impairment, migraine, nervousness, panic disorder, paresthesia, peripheral neuropathy, sleep disorder, somnolence, tremor, vertigo;

Respiratory: dyspnea, epistaxis, nasal congestion, pharyngeal discomfort, respiratory congestion, rhinitis, sinus disorder;

Skin: alopecia, dermatitis, dry skin, ecchymosis, erythema, flushing, photosensitivity, pruritus, sweating, urticaria;

Special Senses: blurred vision, burning/stinging in the eye, conjunctivitis, decrease in visual acuity, taste perversion, tinnitus;

Urogenital: impotence, nocturia, urinary frequency, urinary tract infection.

Hydrochlorothiazide

Other adverse experiences that have been reported with hydrochlorothiazide, without regard to causality, are listed below:

Body as a Whole: weakness; Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation;

Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia;

Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema;

Metabolic: hyperglycemia, glycosuria, hyperuricemia;

Musculoskeletal: muscle spasm;

Nervous System/Psychiatric: restlessness; Renal: renal failure, renal dysfunction, interstitial nephritis;

Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis;

Special Senses: transient blurred vision, xanthopsia.

Persistent dry cough (with an incidence of a few percent) has been associated with ACE-inhibitor use and in practice can be a cause of discontinuation of ACE-inhibitor therapy. Two prospective, parallel-group, double-blind, randomized, controlled trials were conducted to assess the effects of losartan on the incidence of cough in hypertensive patients who had experienced cough while receiving ACE-inhibitor therapy. Patients who had typical ACE-inhibitor cough when challenged with lisinopril, whose cough disappeared on placebo, were randomized to losartan 50 mg, lisinopril 20 mg, or either placebo (one study, n=97) or 25 mg hydrochlorothiazide (n=135). The double-blind treatment period lasted up to 8 weeks. The incidence of cough is shown below.

† Demographics = (89% Caucasian, 64% female)

†† Demographics = (90% Caucasian, 51% female)

These studies demonstrate that the incidence of cough associated with losartan therapy, in a population that all had cough associated with ACE-inhibitor therapy, is similar to that associated with hydrochlorothiazide or placebo therapy.

Cases of cough, including positive re-challenges, have been reported with the use of losartan in post-marketing experience.

Severe Hypertension

In a clinical study in patients with severe hypertension (SiDBP ≥110 mmHg), the overall pattern of adverse events reported through six weeks of follow-up was similar in patients treated with losartan/hydrochlorothiazide as initial therapy and in patients treated with losartan as initial therapy. There were no reported cases of syncope in either treatment group. There were 2 (0.6%) and 0 (0.0%) cases of hypotension reported in the group treated with losartan/hydrochlorothiazide and the group treated with losartan, respectively. There were 3 (0.8%) and 2 (1.2%) cases of increased serum creatinine (>0.5 mg/dL) in the group treated with losartan/hydrochlorothiazide and the group treated with losartan, respectively, during the same time period.

Post-Marketing Experience

The following additional adverse reactions have been reported in post-marketing experience:

Digestive: Hepatitis has been reported rarely in patients treated with losartan.

Hemic: Thrombocytopenia.

Hypersensitivity: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schönlein purpura, has been reported with losartan. Anaphylactic reactions have been reported.

Metabolic and Nutrition: Hyperkalemia, hyponatremia have been reported with losartan.

Musculoskeletal: Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Respiratory: Dry cough (see above) has been reported with losartan.

Skin: Erythroderma has been reported with losartan.

Laboratory Test Findings

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of losartan/hydrochlorothiazide.

Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in 0.6 and 0.8 percent, respectively, of patients with essential hypertension treated with losartan/hydrochlorothiazide alone. No patient discontinued taking losartan/hydrochlorothiazide due to increased BUN. One patient discontinued taking losartan/hydrochlorothiazide due to a minor increase in serum creatinine.

Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.14 grams percent and 0.72 volume percent, respectively) occurred frequently in patients treated with losartan/hydrochlorothiazide alone, but were rarely of clinical importance. No patients were discontinued due to anemia.

Liver Function Tests: Occasional elevations of liver enzymes and/or serum bilirubin have occurred. In patients with essential hypertension treated with losartan/hydrochlorothiazide alone, no patients were discontinued due to these laboratory adverse experiences.

9. OVERDOSAGE

Losartan Potassium

Significant lethality was observed in mice and rats after oral administration of 1000 mg/kg and 2000 mg/kg, respectively, about 44 and 170 times the maximum recommended human dose on a mg/m2 basis.

Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.

Neither losartan nor its active metabolite can be removed by hemodialysis.

Hydrochlorothiazide

The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats. The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.

10. DRUG INTERACTIONS

Losartan Potassium

No significant drug-drug pharmacokinetic interactions have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. Rifampin, an inducer of drug metabolism, decreased the concentrations of losartan and its active metabolite. (See Drug Interactions.) In humans, two inhibitors of P450 3A4 have been studied. Ketoconazole did not affect the conversion of losartan to the active metabolite after intravenous administration of losartan, and erythromycin had no clinically significant effect after oral administration. Fluconazole, an inhibitor of P450 2C9, decreased active metabolite concentration and increased losartan concentration. The pharmacodynamic consequences of concomitant use of losartan and inhibitors of P450 2C9 have not been examined. Subjects who do not metabolize losartan to active metabolite have been shown to have a specific, rare defect in cytochrome P450 2C9. These data suggest that the conversion of losartan to its active metabolite is mediated primarily by P450 2C9 and not P450 3A4.

As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.

Lithium: As with other drugs which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be co-administered with angiotensin II receptor antagonists.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors: In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists (including losartan) may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving losartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including losartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors.

Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on losartan/hydrochlorothiazide and other agents that affect the RAS.

Do not co-administer aliskiren with losartan/hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with losartan/hydrochlorothiazide in patients with renal impairment (GFR <60 ml/min).

Hydrochlorothiazide

When administered concurrently, the following drugs may interact with thiazide diuretics:

Alcohol, barbiturates, or narcotics — potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulin) — dosage adjustment of the antidiabetic drug may be required.

Other antihypertensive drugs — additive effect or potentiation.

Cholestyramine and colestipol resins — Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.

Corticosteroids, ACTH — intensified electrolyte depletion, particularly hypokalemia.

Pressor amines (e.g., norepinephrine) — possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) — possible increased responsiveness to the muscle relaxant.

Lithium — should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with losartan/hydrochlorothiazide.

Non-steroidal Anti-inflammatory Drugs including Selective Cyclooxygenase-2 Inhibitors — The administration of a non-steroidal anti-inflammatory agent, including a selective cyclooxygenase-2 inhibitor, can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when losartan/hydrochlorothiazide and non-steroidal anti-inflammatory agents, including selective cyclooxygenase-2 inhibitors, are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

In patients receiving diuretic therapy, co-administration of NSAIDs with angiotensin receptor blockers, including losartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving hydrochlorothiazide, losartan, and NSAID therapy.

11. PHARMACOKINETICS

11.1 Losartan Potassium

Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. Losartan metabolites have been identified in human plasma and urine. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. Following oral and intravenous administration of 14C-labeled losartan potassium, circulating plasma radioactivity is primarily attributed to losartan and its active metabolite. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites. Minimal conversion of losartan to the active metabolite (less than 1% of the dose compared to 14% of the dose in normal subjects) was seen in about one percent of individuals studied.

The terminal half-life of losartan is about 2 hours and of the metabolite is about 6-9 hours.

The pharmacokinetics of losartan and its active metabolite are linear with oral losartan doses up to 200 mg and do not change over time. Neither losartan nor its metabolite accumulate in plasma upon repeated once-daily dosing.

Following oral administration, losartan is well absorbed (based on absorption of radiolabeled losartan) and undergoes substantial first-pass metabolism; the systemic bioavailability of losartan is approximately 33%. About 14% of an orally-administered dose of losartan is converted to the active metabolite. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its Cmax but has only minor effects on losartan AUC or on the AUC of the metabolite (about 10% decreased).

The pharmacokinetics of losartan and its active metabolite were also determined after IV doses of each component separately in healthy volunteers. The volume of distribution of losartan and the active metabolite is about 34 liters and 12 liters, respectively. Total plasma clearance of losartan and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with renal clearance of about 75 mL/min and 25 mL/min, respectively. After single doses of losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its metabolites. Following oral 14C-labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of 14C-labeled losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces.

Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.

11.2 Hydrochlorothiazide

After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.

Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

11.3 Special Populations

Pediatric: Pharmacokinetics of losartan and its active metabolite were generally similar across the studied age groups and similar to historical pharmacokinetic data in adults.

The bioavailability of the suspension formulation was compared with losartan tablets in healthy adults. The suspension and tablet are similar in their bioavailability with respect to both losartan and the active metabolite (see DOSAGE AND ADMINISTRATION).

Geriatric and Gender: Losartan pharmacokinetics have been investigated in the elderly (65-75 years) and in both genders. Plasma concentrations of losartan and its active metabolite are similar in elderly and young hypertensives. Plasma concentrations of losartan were about twice as high in female hypertensives as male hypertensives, but concentrations of the active metabolite were similar in males and females. No dosage adjustment is necessary (see DOSAGE AND ADMINISTRATION).

Race: Pharmacokinetic differences due to race have not been studied (see also PRECAUTIONS).

Renal Insufficiency:

Losartan: Following oral administration, plasma concentrations and AUCs of losartan and its active metabolite are increased by 50-90% in patients with mild (creatinine clearance of 50 to 74 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal insufficiency. In this study, renal clearance was reduced by 55-85% for both losartan and its active metabolite in patients with mild or moderate renal insufficiency. Neither losartan nor its active metabolite can be removed by hemodialysis. No dosage adjustment is necessary for patients with renal impairment unless they are volume-depleted (see WARNINGS, Hypotension — Volume-Depleted Patients and DOSAGE AND ADMINISTRATION).

Hydrochlorothiazide: Following oral administration, the AUC for hydrochlorothiazide is increased by 70 and 700% for patients with mild and moderate renal insufficiency, respectively. In this study, renal clearance of hydrochlorothiazide decreased by 45 and 85% in patients with mild and moderate renal impairment, respectively.

The usual regimens of therapy with losartan/hydrochlorothiazide may be followed as long as the patient's creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so losartan/hydrochlorothiazide is not recommended. (See DOSAGE AND ADMINISTRATION.)

Hepatic Insufficiency: Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-times and about 1.7-times those in young male volunteers. Compared to normal subjects the total plasma clearance of losartan in patients with hepatic insufficiency was about 50% lower and the oral bioavailability was about 2-times higher. A lower starting dose is recommended for patients with a history of hepatic impairment (see DOSAGE AND ADMINISTRATION).

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How available:

a) Brand name: HYZAAR, by MERCK.

b) Generic drugs: Losartan Potassium and Hydrochlorothiazide, by various manufacturers.

2) How supplied:

Losartan Potassium and Hydrochlorothiazide Tablets (by Mylan Pharm) are available containing 50 mg or 100 mg of losartan potassium, USP and 12.5 mg or 25 mg of hydrochlorothiazide, USP, providing for the following available combinations: 50 mg/12.5 mg, 100 mg/12.5 mg and 100 mg/25 mg.

The 50 mg/12.5 mg tablets are light yellow film-coated, oval, unscored tablets debossed with M on one side of the tablet and LH4 on the other side. They are available as follows:

NDC 0378-1418-93 bottles of 30 tablets

NDC 0378-1418-77 bottles of 90 tablets

NDC 0378-1418-10 bottles of 1000 tablets

The 100 mg/12.5 mg tablets are orange film-coated, oval, unscored tablets debossed with M on one side of the tablet and LH5 on the other side. They are available as follows:

NDC 0378-1419-93 bottles of 30 tablets

NDC 0378-1419-77 bottles of 90 tablets

NDC 0378-1419-10 bottles of 1000 tablets

The 100 mg/25 mg tablets are light yellow film-coated, oval, unscored tablets debossed with M on one side of the tablet and LH6 on the other side. They are available as follows:

NDC 0378-1420-93 bottles of 30 tablets

NDC 0378-1420-77 bottles of 90 tablets

NDC 0378-1420-10 bottles of 1000 tablets

3) Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Keep container tightly closed. Protect from light.

Rx only

Rev 03/13